Migraine headaches are known to produce the most intense headaches reported. The pathophysiology of migraine headaches involve vasoconstriction and vasodilation. A variety of stress stimuli, including intense light, noise, anxiety, exertion, extremes of temperature, hormones, exhaustion, infection and trauma result in constriction of extracranial blood vessels. The vasoconstriction is followed by reflexive or sequential vasodilation, which subsequently spreads to intracranial vessels. It is during this latter phase that the patient feels the intense, throbbing headache characteristic of migraines. Increased levels of norepinephrine, serotonin, histamine, and the neuropeptides bradykinin and substance P, in addition to products of tissue anoxia, are considered to be the main endogenous pain producing molecules, accompanied by direct sensory nerve stimulation because of the stretching that accompanies vasoconstriction and dilation.
Mast cells, normal components of connective tissues, are thought to play an important role in the development of migraine headaches (see, e.g., Theoharides, U.S. Pat. No. 5,250,529). Each mast cell contains as many as 500 secretory granules, each storing over 20 different kinds of biochemicals, including histamine, neuropeptide kinins, prostagandims PGP.sub.2, PGD.sub.4, leukotriene C.sub.4, and serotonin which are vasoconstrictive, as well as vasodilatory, vasoactive intestinal polypeptide, tumor necrosis factor and nitric oxide. Degranulation of mast cells, which is defined herein as the release of any or all biochemicals from secretory granules to the local tissue area or circulation, for whatever reason in whatever sequence, occurs in response to interaction of various agents with specific mast cell surface receptors or other binding proteins. The best known of these receptors is the one for immunoglobulin E (IgE). There is also evidence that neurotransmitters such as acetylcholine and neuropeptides, released from neurons, and female sex hormones (estradiol) may also trigger mast cell degranulation through specific receptors, especially in response to stress. Other known triggers include viruses, bacterial toxins, drugs such as aspirin, morphine and curare, radiological contrast media, extremes of temperature, solar radiation, etc. A method of alleviating or preventing a migraine headache comprising the administration of a direct mast cell degranulation blocking agent during the prodromal phase of the migraine and in the absence of an analgesic is the subject of the aforementioned U.S. Pat. No. 5,250,529.
Stress is long known to activate the hypothalamic-pituitary-adrenal axis and can affect illness, especially autoimmune and neuroinflammatory syndromes. These effects may be mediated both through psychoneuroimmune and neuroendocrine-immune interactions which contribute to inflammation and inflammatory diseases. Stress precipitates or worsens certain neuroinflammatory conditions such as migraines (Theoharides, Prospect. Biol. Med., 26:672 (1983)), and interstitial cystitis (Sant et al., Urol. Clin. North Amer., 21:41-53, (1994)), both of which have been associated with mast cell activation. Mast cells are necessary for the development of allergic and late phase reactions, but may be involved in inflammation as they release numerous cytokines (Galli, N. Eng. J. Med., 328:257 (1993)). Mast cells have also been found in close apposition to neurons and, as noted above, are activated by neuropeptides, as well as by antidromic nerve stimulation in the dura. Moreover, mast cell secretion of histamine occurs after repetitive exposure to odors, after Pavlovian conditioning and in response to isolation stress (Bugajski et al., Agents Actions, 41:C75-76 (1994)). These findings have raised speculations that mast cells may be involved in neuroimmunoendocrine physiology (Stead et al., in Burger et al., eds. Cell to Cell Interaction, Karger, Basel, 1990, pp 170-187) and pathology (Theoharides, Life Sci., 46:607 (1990)).
It is, therefore, an object of this invention to describe the biochemical and anatomical link between stress and the development of migraine headaches, and to provide pharmaceutical means for disrupting this link.